Hippocrates, the father of modern medicine who lived between 460 and 377 B.C., had records of a powder made from the bark and leaves of the willow tree that would relieve headache pain and fever. Over the centuries, this natural remedy evolved into the wonder drug commonly known as aspirin. Nearly 2,000 years later, a physician named Lawrence Craven determined that none of his 8,000 male patients who took a daily aspirin for six years had suffered a heart attack. Although his study took place in the early 1950s, the Food and Drug Administration (FDA) did not approve the use of aspirin to prevent recurrent heart attack and stroke until 1985. Today, new data show that aspirin is an effective treatment for strokes, certain vascular conditions and rheumatologic diseases. It also has been linked to the prevention of pre-cancerous growths in the colon and common complications of diabetes resulting from impaired blood circulation. Aspirin is just one of the countless crossover drugs now used to treat diseases or symptoms far beyond their original intent. Many have been proven effective for seemingly disparate, but often related, biological systems or disease states. Cancer and autoimmune disorders Several chemotherapy drugs that have been successful for the treatment of cancer have become crossover drugs that are now used in the treatment of specific autoimmune disorders and viruses, says Stan Louie, Pharm.D., Ph.D., associate professor of clinical pharmacy at the USC School of Pharmacy. One cancer drug is methotrexate, now commonly used to treat autoimmune disorders such as rheumatoid arthritis (RA), psoriatic arthritis and lupus. Autoimmune disorders cause a person’s immune system to attack itself, causing pain or inflammation in or around the tissues, bones and muscles surrounding the joints. In these diseases, immune cells are replicating quickly, which causes overly reactive white blood cells to attack connective tissue, Louie says. ?Low doses of methotrexate affect specific types of white blood cells, called macrophages, which engulf foreign material in the body and initiate the autoimmune response,? he says. ?Methotrexate suppresses these macrophages, making it possible to lessen or prevent an autoimmune reaction, thus reducing inflammation and pain.? Adds Nouri Neamati, Ph.D., assistant professor of pharmaceutical sciences at the USC School of Pharmacy, ?Methotrexate’s secondary benefits were discovered when cancer patients with RA began to see a remarkable reduction in joint pain and inflammation. Researchers generally do not know about secondary therapeutic uses for a drug until it gets to patients in the clinic.? Cancer and osteoporosis The advent of the selective estrogen receptor modulators (SERMs)?such as tamoxifen and raloxifene?has strengthened medical practitioners’ arsenal against both breast cancer and osteoporosis. SERMs work by binding to selective estrogen receptors in the bones just like estrogen does, and at the same time, they block the effects of estrogen on breast tissue. ?Estrogen is a stimulating growth factor for certain kinds of breast cancers, and long-term use has been correlated with an increased risk of uterine cancer,? Louie says. ?An ideal SERM would block the negative effects of estrogen on breast and uterine tissue, while enhancing its effect on a patient’s skeletal and cardiovascular system.? The FDA has approved tamoxifen for the prevention and treatment of breast cancer in women who are at high risk for the disease. An unfortunate drawback to tamoxifen is an increased risk of uterine cancer and blood clots for women. Although it is thought to help protect bone density, tamoxifen has not been approved to prevent osteoporosis, he says. On the other hand, the FDA has approved raloxifene for the prevention of osteoporosis. Its crossover application?deterring cancer?became apparent during testing for its activity against osteoporosis, Louie says. ?It was determined that women in the anti-osteoporotic study of raloxifene developed fewer breast cancer tumors without an increased risk of uterine cancer,? he says. ?This sparked the idea for a clinical trial to quantify raloxifene’s effect on cancer prevention.? The Study of Tamoxifen and Raloxifene (STAR) clinical trials are currently underway at cancer centers across the country, including the USC/Norris Comprehensive Cancer Center. Principal investigator Darcy Spicer, M.D., associate professor of clinical medicine at the Keck School of Medicine, is following postmenopausal women who are at high risk for breast cancer to determine if raloxifene is as effective in preventing breast cancer as tamoxifen has proven to be. The STAR clinical trials are set to end in 2004. If raloxifene is found to protect against both breast cancer and osteoporosis, it may replace tamoxifen as a therapeutic option for the prevention of these diseases, Louie says. Cancer and COX-2 inhibitors Studies of the long-term use of Vioxx and Celebrex, anti-inflammatory drugs known as COX-2 inhibitors that are commonly used to fight the pain of arthritis, also have shown a decreased risk of colorectal cancer. Hormones called prostaglandins deliver pain signals and induce inflammation in the body. Central to the production of prostaglandins is an enzyme called cyclooxygenase (COX) that is broken down into two key parts: COX-1 and COX-2. ?While COX-1 is central to protective functions in the gastrointestinal tract and kidneys, COX-2 seems to be responsible for triggering pain and inflammatory responses,? Neamati explains. ?Because COX-2 is easy to stimulate, it has been effective to create drugs that are selective to blocking this portion of the COX enzyme. COX-2 inhibitors reduce pain and inflammation, without unpleasant side effects.? He adds, ?Research shows that if you have genetically altered mice with a COX-2 deficiency, they develop far fewer intestinal tumors when injected with cancerous cells. There is also some indication that COX-2 inhibitors may be effective in preventing breast, bladder and lung cancers.? After this initial research outcome, researchers also found that long-term use of COX-2 inhibitors is associated with a reduction in colorectal polyps in patients with a disease called Familial Adenomatous Polyposis (FAP). FAP is an inherited disease in which the inside of the rectum and colon are covered with many polyps that can become cancerous. Neamati adds, ?In 10 years we will have conclusive data about COX-2 inhibitors’ effects on the prevention of particular cancers. Although they are not currently approved for this use, some physicians are recommending that patients at a high risk for some cancers take a low dose of either Celebrex or Vioxx once a day.” Medical practitioners continue to discover secondary?and even broader?therapeutic uses for well-known drugs. Although there may be anecdotal evidence, it takes time for investigators to do controlled studies on each substance, and even longer to gain FDA approval to market the drug for additional uses. But as the treatment applications of drugs increase, the options for both patients and physicians continue to grow.
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